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Pathogenesis and regulation mechanisms for Th1- and Th2-dependent allergic airway inflammation

Th1和Th2依赖性过敏性气道炎症的发病机制和调控机制

基本信息

批准号：
18604001
负责人：
NISHIMURA Takashi
金额：
$ 2.5万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

To overcome various immune diseases induced by disruption of type1/type2 immune balance, we have established Th1- or Th2-dependent immune diseases models. In the present project, we established allergic airway inflammation mouse models by adoptive transfer of antigen-specific Th1 or Th2 cells followed by the antigen inhalation and investigated precise cellular regulation and molecular mechanisms in the pathogenesis. In the present models, transfer of Th1 cells induced fatal airway hyperresponsiveness (AHR) associated with severe neutrophilia, whereas the cased of Th2 cells caused eosinophilia in the lung. Compared to the Th2-transferred model, mRNA expression levels of MUC5AC and Gob5, related to mucus hypersecretion in airway epithelium, were extremely lower in the Th1 -transferred model. Thus, it was demonstrated that the Th1-induced AHR was independent on such mucus hypersecretion, which was essential for elevation of AHR in Th2-mediated asthma. In the Th2-transferred model, we foun … More d that in vivo injection of TLR9 ligand, CpG remarkably suppressed the symptoms by blocking of Th2-cell migration into lung. To investigate the mechanism, we used IFN-γ knockout mice and neutralizing antibodies against type I cytokines such as IFN-α, β, and IL-12. As the results, IFN-α, β, and IL-12, but not IFN-γ, were required for the inhibitory effect of CpG on Th2-cell migration. These findings were highly valued for elucidation of the suppression mechanism mediated by down-regulation of Th2-cell migration into lung even at effector phase, suggesting that CpG would be expected as a tool for clinical application in Th2-dependent asthma.Furthermore, we evaluated inhibitory effects of lactic acid bacterium (LAB), which easily activate type1 immunity, on Th2-dependent asthma. As the results, it was suggested that oral intake of LAB may have preventative effects on the allergic inflammation at induction phase rather than therapeutic effects at effector phase. The present findings will contribute to elucidation of the pathogenesis and development of the proper regulation in allergic airway inflammation. Less

为了克服1型/2型免疫平衡被破坏所引起的各种免疫疾病，我们建立了Th 1或Th 2依赖性免疫疾病模型。本课题通过过继性输注抗原特异性Th 1或Th 2细胞，并吸入抗原，建立小鼠过敏性气道炎症模型，研究其发病机制中的细胞调控和分子机制。在目前的模型中，Th 1细胞的转移诱导致命的气道高反应性（AHR）与严重的嗜酸性粒细胞增多症，而Th 2细胞的情况下，导致在肺嗜酸性粒细胞增多症。与Th 2转移模型相比，与气道上皮粘液高分泌相关的MUC 5AC和Gob 5的mRNA表达水平在Th 1转移模型中极低。因此，证明了Th 1诱导的AHR不依赖于这种粘液高分泌，而粘液高分泌对于Th 2介导的哮喘中AHR的升高是必需的。在Th 2转移模型中，我们发现， ...更多信息体内注射TLR 9配体、CpG可通过阻断Th 2细胞向肺内的迁移而显著抑制上述症状。为了研究机制，我们使用IFN-γ敲除小鼠和针对I型细胞因子（如IFN-α、β和IL-12）的中和抗体。结果表明，CpG对Th 2细胞迁移的抑制作用需要IFN-α、IFN-β和IL-12，而不是IFN-γ。这些发现对于阐明即使在效应期也通过下调Th 2细胞向肺内迁移介导的抑制机制具有高度价值，提示CpG有望作为一种工具在Th 2依赖性哮喘的临床应用中发挥作用。此外，我们评估了易激活1型免疫的乳酸菌（LAB）对Th 2依赖性哮喘的抑制作用。结果提示，口服乳酸菌可能在诱导期对过敏性炎症有预防作用，而在效应期没有治疗作用。本研究结果将有助于阐明过敏性气道炎症的发病机制和发展的适当调节。少